Medical adhesives for stopping heavy bleeding and sealing leakages

ABSTRACT

The present invention relates to a method that includes providing a formulation having an isocyanate-functional prepolymer and a curing component comprising an amino-functional aspartic ester of the general formula (I) 
     
       
         
         
             
             
         
       
     
     applying the formulation to a cell tissue; and curing the formulation such that the loss of blood (haemostatic) or tissue fluids is staunched or leaks in cell tissues are sealed.

The present invention relates to innovative, quick-curing adhesivesbased on hydrophilic polyisocyanate prepolymers and intended for use inemergency care for staunching severe bleeding (haemorrhage) and sealingleaks.

A variety of materials used as tissue adhesives are availablecommercially. They include the cyanoacrylates Dermabond® (octyl2-cyanoacrylate) and Histoacryl Blue® (butyl cyanoacrylate). Arequirement for efficient bonding of the cyanoacrylates are drysubstrates. In cases of severe bleeding the adhesive fails.

As an alternative to the cyanoacrylates there are biological adhesivesavailable such as, for example, BioGlue®, a mixture of glutaraldehydeand bovine serum albumen, a variety of collagen- and gelatine-basedsystems (FloSeal®) and also the fibrin adhesives (Tissucol). Thesesystems serve primarily for haemostasis (stopping bleeding). Apart fromthe high costs, fibrin adhesives are notable for a relatively weakadhesion and a rapid breakdown, and so can be used only in cases ofrelatively minor injury on unstretched tissue. Collagen- andgelatine-based systems such as FloSeal® serve exclusively forhaemostasis. Moreover, because fibrin and thrombin are obtained fromhuman material, and collagen and gelatine from animal material, there isalways a risk of infection in biological systems. Furthermore,biological materials must be given refrigerated storage, and so theiruse in emergency care such as in disaster zones, for example, or in thecase of military deployment, etc., is not possible. In these cases thereare QuikClot® or QuikClot ACS+™ available to treat traumatic wounds,QuikClot being a granular mineral which in an emergency is inserted intothe wound, where it leads to coagulation as a result of removal ofwater. In the case of QuikClot® this is a highly exothermic reaction,leading to burns. QuikClot ACS+™ is a gauze into which the salt has beenembedded. For haemostasis the system must be pressed firmly onto thewound.

The possible application of polyurethane prepolymers as a haemostatic isaddressed in the articles “Isocyanate-terminated urethane prepolymer asbioadhesive material: evaluation of bioadhesion and biocompatibility, invitro and in vivo assays” (Journal of Biomaterials Science, PolymerEdition (2001), 12(7), 707-719) and “Development of a biodegradablebioadhesive containing urethane groups” (Journal of Materials Science:Materials in Medicine (2008), 19(1), 111-120).

It has now been found that formulations comprising specific hydrophilicpolyurethane prepolymers and amino-functional curing agents can be usedwith outstanding effect as a haemostatic for stopping blood. Inaddition, the formulations have an advantageous adhesive quality, andso, as well as stopping blood, the effect is achieved at the same timeof the fixing of the film formed by the formulation on the injury site.Furthermore, by this means, particularly in the case of relativelysevere injury, sections of tissue can be joined to one another again andfixed, which is advantageous for the would healing process.

The present invention accordingly provides for the use of formulationscomprising

A) isocyanate-functional prepolymers obtainable from

-   -   A1) aliphatic isocyanates and    -   A2) polyols having number-average molecular weights of ≧400        g/mol and average OH functionalities of 2 to 6,

B) a curing component comprising

-   -   B1) amino-functional aspartic esters of the general formula (I)

-   -   where    -   X is an n-valent organic radical obtained by removing the        primary amino groups of an n-functional amine,    -   R₁ and R₂ are identical or different organic radicals which        contain no Zerewitinoff-active hydrogen and    -   n is an integer of at least 2        and    -   B2) optionally, organic fillers which have a viscosity as        measured to DIN 53019 at 23° C. in the range from 10 to 6000        mPas        and

C) optionally, reaction products of isocyanate-functional prepolymers asdefined for component A) with aspartic esters as per component B1)and/or organic fillers as per component B2)

to staunch the loss of blood (haemostatic) or tissue fluids or to sealleakages in cell tissues.

Likewise provided by the present invention is the use of aforementionedformulations for producing a composition for staunching the loss ofblood (haemostatic) or tissue fluids or for sealing leaks in celltissues.

Likewise provided by the invention is a method of staunching the loss ofblood (haemostatic) or tissue fluids or for sealing leaks in celltissues, by applying the formulations that are essential to theinvention to a cell tissue and then curing them.

The staunching, essential to the invention, of the loss of fluid orblood or the sealing of leaks in cell tissues can be carried out both invivo and in vitro.

For the definition of Zerewitinoff-active hydrogen, refer to RömppChemie Lexikon, Georg Thieme Verlag Stuttgart. Groups withZerewitinoff-active hydrogen comprehend, preferably, OH, NH or SH.

Tissue or cell tissue is understood in the context of the presentinvention to refer to associations of cells which consist of cells ofthe same form and function, such as surface tissue (skin), epithelialtissue, myocardial, connective or stromal tissue, muscles, nerves andcartilage. This also includes, among other systems, all organs made upof associations of cells, such as the liver, kidneys, lungs, heart, etc.

The isocyanate-functional prepolymers used in A) are obtainable byreacting isocyanates with hydroxyl-functional polyols, with the optionaladdition of catalysts and also auxiliaries and additives.

Examples of isocyanates which can be used in A1) include monomericaliphatic or cycloaliphatic di- or triisocyanates such as 1,4-butylenediisocyanate (BDI), 1,6-hexamethylene diisocyanate (HDI), isophoronediisocyanate (IPDI), 2,2,4- and/or 2,4,4-trimethylhexamethylenediisocyanate, the isomeric bis(4,4′-isocyanatocyclohexyl)methanes ortheir mixtures of any desired isomer content, 1,4-cyclohexylenediisocyanate, 4-isocyanatomethyl-1,8-octane diisocyanate (nonanetriisocyanate), and also alkyl 2,6-diisocyanatohexanoates (lysinediisocyanate) with C1-C8 alkyl groups.

Besides the abovementioned monomeric isocyanates it is also possible touse their higher molecular mass derivatives with uretdione,isocyanurate, urethane, allophanate, biuret, iminooxadiazinedione oroxadiazinetrione structure and also mixtures thereof.

In A1) it is preferred to use isocyanates of the aforementioned kindhaving exclusively aliphatically or cycloaliphatically attachedisocyanate groups or mixtures thereof.

The isocyanates or isocyanate mixtures used in A1) preferably have anaverage NCO functionality of 2 to 4, more preferably 2 to 2.6 and verypreferably 2 to 2.4.

In one particularly preferred embodiment hexamethylene diisocyanate isused in A1).

For the synthesis of the prepolymer in A2) it is possible in principleto use all of the polyhydroxy compounds known per se to the skilledperson that have 2 or more OH functions per molecule. These may be, forexample, polyester polyols, polyacrylate polyols, polyurethane polyols,polycarbonate polyols, polyether polyols, polyester polyacrylatepolyols, polyurethane polyacrylate polyols, polyurethane polyesterpolyols, polyurethane polyether polyols, polyurethane polycarbonatepolyols, polyester polycarbonate polyols or any desired mixtures thereofwith one another.

The polyols used in A2) preferably have an average OH functionality of 3to 4.

The polyols used in A2) further preferably have a number-averagemolecular weight of 400 to 20 000 g/mol, more preferably 2000 to 10 000g/mol and very preferably 4000 to 8500.

Polyether polyols are preferably polyalkylene oxide polyethers based onethylene oxide and optionally propylene oxide.

These polyether polyols are based preferably on starter molecules with afunctionality of two or more, such as difunctional or higherpolyfunctional alcohols or amines.

Examples of such starters are water (considered to be a diol), ethyleneglycol, propylene glycol, butylene glycol, glycerol, TMP, sorbitol,pentaerythritol, triethanolamine, ammonia or ethylenediamine.

Preferred polyalkylene oxide polyethers correspond to those of theaforementioned kind and contain from 50% to 100%, preferably 60% to 90%,of ethylene oxide-based units, based on the amounts of alkylene oxideunits that are present in total.

Preferred polyester polyols are the polycondensates—known per se—ofdiols and also, optionally, triols and tetraols and of dicarboxylic andalso, optionally, tricarboxylic and tetracarboxylic acids orhydroxycarboxylic acids or lactones. In place of the free polycarboxylicacids it is also possible to use the corresponding polycarboxylicanhydrides or corresponding polycarboxylic esters of lower alcohols forpreparing the polyesters.

Examples of suitable diols are ethylene glycol, butylene glycol,diethylene glycol, triethylene glycol, polyalkylene glycols such aspolyethylene glycol, and also 1,2-propanediol, 1,3-propanediol,butane-1,3-diol, butane-1,4-diol, hexane-1,6-diol and isomers, neopentylglycol or neopentyl glycol hydroxypivalate, preference being given tohexane-1,6-diol and isomers, butane-1,4-diol, neopentyl glycol andneopentyl glycol hydroxypivalate. In addition it is also possible to usepolyols such as trimethylolpropane, glycerol, erythritol,pentaerythritol, trimethylolbenzene or trishydroxyethyl isocyanurate.

As dicarboxylic acids it is possible to use phthalic acid, isophthalicacid, terephthalic acid, tetrahydrophthalic acid, hexahydrophthalicacid, cyclohexanedicarboxylic acid, adipic acid, azelaic acid, sebacicacid, glutaric acid, tetrachlorophthalic acid, maleic acid, fumaricacid, itaconic acid, malonic acid, suberic acid, 2-methylsuccinic acid,3,3-diethylglutaric acid and/or 2,2-dimethylsuccinic acid. Thecorresponding anhydrides can also be used as an acid source.

Where the average functionality of the polyol to be esterified is >than2, it is also possible, additionally, to use monocarboxylic acids, aswell, such as benzoic acid and hexanecarboxylic acid.

Preferred acids are aliphatic or aromatic acids of the aforementionedkind. Particular preference is given to adipic acid, isophthalic acidand phthalic acid.

Hydroxycarboxylic acids, which can be used as reaction participants aswell when preparing a polyester polyol with terminal hydroxyl groups,are, for example, hydroxycaproic acid, hydroxybutyric acid,hydroxydecanoic acid, hydroxystearic acid and the like. Suitablelactones are caprolactone, butyrolactone and homologues. Caprolactone ispreferred.

It is likewise possible to use polycarbonates containing hydroxylgroups, preferably polycarbonate diols, having number-average molecularweights M_(n) of 400 to 8000 g/mol, preferably 600 to 3000 g/mol. Theyare obtainable by reaction of carbonic acid derivatives, such asdiphenyl carbonate, dimethyl carbonate or phosgene, with polyols,preferably diols.

Examples of such diols are ethylene glycol, 1,2- and 1,3-propanediol,1,3- and 1,4-butanediol, 1,6-hexanediol, 1,8-octanediol, neopentylglycol, 1,4-bishydroxymethylcyclohexane, 2-methyl-1,3-propanediol,2,2,4-trimethylpentane-1,3-diol, dipropylene glycol, polypropyleneglycols, dibutylene glycol, polybutylene glycols, bisphenol A andlactone-modified diols of the aforementioned kind.

For prepolymer synthesis it is preferred to use polyether polyols of theaforementioned kind.

For the preparation of the prepolymer the compounds of component A1) arereacted with those of component A2) at an NCO/OH ratio of preferably 4:1to 20:1, more preferably 8:1, and then the fraction of unreactedcompounds of component A1) is separated off by means of appropriatemethods. Typically for this purpose thin-film distillation is used,giving low-residual-monomer products having residual monomer contents ofless than 1%, preferably less than 0.5% and very preferably less than0.1% by weight.

Optionally it is possible, during or after the preparation, to addstabilizers such as benzoyl chloride, isophthaloyl chloride, dibutylphosphate, 3-chloropropionic acid or methyl tosylate.

The reaction temperature is 20 to 120° C., preferably 60 to 100° C.

Preferably in formula (I):

-   -   R₁ and R₂ are identical or different, optionally branched or        cyclic, organic radicals having 1 to 20, preferably 1 to 10,        carbon atoms and containing no Zerewitinoff-active hydrogen,    -   n is an integer from 2 to 4 and    -   X is an n-valent, optionally branched or cyclic, organic radical        having 2 to 20, preferably 5 to 10, carbon atoms and is obtained        by removing the primary amino groups of an n-functional primary        amine

The amino-functional polyaspartic esters B1) are prepared in a known wayby reaction of the corresponding primary, at least difunctional aminesX(NH₂)_(n) with maleic or fumaric esters of the general formula

Preferred maleic or fumaric esters are dimethyl maleate, diethylmaleate, dibutyl maleate and the corresponding fumaric esters.

Preferred primary, at least difunctional amines X(NH₂)_(n) areethylenediamine, 1,2-diaminopropane, 1,4-diaminobutane,1,3-diaminopentane, 1,5-diaminopentane, 2-methyl-1,5-diaminopentane,1,6-diaminohexane, 2,5-diamino-2,5-dimethylhexane, 2,2,4- and/or2,4,4-trimethyl-1,6-diaminohexane, 1,11-diaminoundecane,1,12-diaminododecane, 1-amino-3,3,5-trimethyl-5-aminomethylcyclohexane,2,4- and/or 2,6-hexahydrotolylenediamine, 2,4′- and/or4,4′-diaminodicyclohexylmethane,3,3′-dimethyl-4,4′-diaminodicyclohexylmethane,2,4,4′-triamino-5-methyldicyclohexylmethane and polyetheramines havingaliphatically attached primary amino groups, with a number-averagemolecular weight M_(n) of 148 to 6000 g/mol.

Particularly preferred primary, at least difunctional amines are1,3-diaminopentane, 1,5-diaminopentane, 2-methyl-1,5-diaminopentane,1,6-diaminohexane, 1,13-diamino-4,7,10-trioxatridecane.2-Methyl-1,5-diaminopentane is especially preferred.

Preferably R₁ and R₂ independently of one another are C₁ to C₁₀ alkylradicals, more preferably methyl or ethyl radicals.

In one preferred embodiment of the invention R₁=R₂=ethyl, with X beingbased on 2-methyl-1,5-diaminopentane as the n-functional amine.

Preferably n in formula (I), for the description of the functionality ofthe n-functional amine, is an integer from 2 to 6, more preferably 2 to4.

The preparation of the amino-functional aspartic esters B1) from thestated starting materials is accomplished in accordance with DE-A 69 311633 preferably within the temperature range from 0 to 100° C., thestarting materials being employed in proportions such that for eachprimary amino group there is at least one, preferably precisely one,olefinic double bond, and, after the reaction, any starting materialsused in excess can be separated off by distillation. The reaction maytake place in bulk or in the presence of suitable solvents such asmethanol, ethanol, propanol or dioxane or mixtures of such solvents.

The organic liquid fillers used in B2) are preferably non-cytotoxic whentheir cyctotoxicity is measured in accordance with ISO 10993.

As organic fillers it is possible for example to use liquid polyethyleneglycols such as PEG 200 to PEG 600, their monoalkyl and/or dialkylethers such as PEG 500 dimethyl ether, liquid polyether polyols andpolyester polyols, liquid polyesters such as Ultramoll (Lanxess AG,Leverkusen, DE) and also glycerol and its liquid derivatives such astriacetin (Lanxess AG, Leverkusen, DE), for example.

The organic fillers of component B2) are preferably hydroxyl- oramino-functional compounds, preferably purely hydroxyl-functionalcompounds. Preferred purely hydroxyl-functional compounds are polyetherpolyols and/or polyester polyols, more preferably polyether polyols.

The preferred organic fillers of component B2) preferably possessaverage OH functionalities of 1.5 to 3, more preferably 1.8 to 2.2, verypreferably 2.0.

The preferred organic fillers of component B2) preferably possessrepeating units derived from ethylene oxide.

The viscosity of the organic fillers of component B2) is preferably 50to 4000 mPas at 23° C. as measured to DIN 53019.

In one preferred embodiment of the invention polyethylene glycols areused as organic fillers of component B2). They preferably have anumber-average molecular weight of 100 to 1000 g/mol, more preferably200 to 400 g/mol.

The weight ratio of B1) to B2) is 1:0 to 1:20, preferably 1:0 to 1:12.

The weight ratio of component B2, based on the total amount of themixture of B1, B2 and A, is situated in the range from 0 to 100%,preferably 0 to 60%.

In order further to reduce the average equivalent weight of thecompounds used in total for prepolymer crosslinking, based on theNCO-reactive groups, it is also possible, in addition to the compoundsused in B1) and B2), to prepare the amino- or hydroxyl-functionalreaction products of isocyanate-functional prepolymers with asparticesters and/or organic fillers B2), where the latter are amino- orhydroxyl-functional, in a separate preliminary reaction and then to usethem as a relatively high molecular weight curing component C).

In the pre-extension it is preferred to use ratios ofisocyanate-reactive groups to isocyanate groups of 50:1 to 1.5:1, morepreferably 15:1 to 4:1.

The isocyanate-functional prepolymer to be used for this purpose maycorrespond to that of component A) or else, alternatively, may beconstructed of the components listed as possible constituents of theisocyanate-functional prepolymers in the context of this specification.

An advantage of this modification by pre-extension is that theequivalent weight and equivalent volume of the curing component can bemodified within clear limits. As a result, it is possible to carry outapplication using commercially available 2-chamber metering systems, togive an adhesive system which, with existing proportions of the chambervolumes, can be adjusted to the desired ratio of NCO-reactive groups toNCO groups.

If necessary it is possible to colour one of the two components.

The formulations essential to the invention are obtained by mixing theprepolymer with the curing component B) and/or C). In component B)and/or C) there may also be a biologically active component D). Theratio of NCO-reactive NH groups to free NCO groups is preferably 1:1.5to 1:1, more preferably 1:1.

Immediately after the mixing of the individual components with oneanother, the formulations essential to the invention possess a shearviscosity at 23° C. of preferably 1000 to 10 000 mPas, more preferably2000 to 8000 mPas and very preferably 2500 to 5000 mPas.

The rate at 23° C. until complete crosslinking and curing of theadhesive is achieved is typically 30 s to 10 min, preferably 1 min to 8min.

The formulations essential to the invention can be applied forstaunching the loss of blood and tissue fluids and also for sealingleaks in the human or animal body, and also as a tissue adhesive,preference being given to their in vivo application, for example, foremergency treatment in the case of polytrauma after accidents oroperations.

EXAMPLES

Unless indicated otherwise, all percentages are by weight.

PEG=polyethylene glycol

Example 1 Prepolymer A

465 g of EMI and 2.35 g of benzoyl chloride were charged to a 1 lfour-necked flask. Over the course of 2 h at 80° C. 931.8 g of apolyether having an ethylene oxide content of 71% and a propylene oxidecontent of 29% (based in each case on the total alkylene oxide content),prepared starting from TMP (3-functional), were added, with subsequentstirring for 1 h. Subsequently the excess HDI was removed by thin-filmdistillation at 130° C. and 0.1 torr. This gave 980 g (71%) of theprepolymer, with an NCO content of 2.53%. The residual monomer contentwas <0.03% HDI.

Example 2 Aspartate B

Under a nitrogen atmosphere 2 mol of diethyl maleate were slowly admixeddropwise with 1 mol of 2-methyl-1,5-diaminopentane, at a rate such thatthe reaction temperature did not exceed 60° C. Subsequently the mixturewas heated to 60° C. until diethyl maleate was no longer detectable inthe reaction mixture. The product was purified by distillation.

Example 3 Application of the Formulations Essential to the Invention forStaunching Severe Bleeding and Sealing Leaks

The formulations essential to the invention were applied by means of acommercial two-chamber applicator with static mixer. One chambercontained a mixture of 0.45 g of PEG 200 and 0.55 g of aspartate B. Thesecond chamber contained 4 g of prepolymer A. Pressing down on the ramresulted in mixing of the two components.

In vivo experiments on haemostasis—animal model: rat

The experiment was carried out with a Wistar rat weighing 350 grams.Anaesthesia was induced with diethyl ether and subsequently,intraperitoneally, using ketamine/xylazine. Subsequently the trachea wasintubated with a 14-gauge venous catheter. Ventilation was carried outwith an air/oxygen mixture (FiO2=0.5). The rat was fixed to a heatedsupport. Preparation for surgery was carried out aseptically and withlocal infiltration of lidocaine.

The abdomen was opened up by means of anterior longitudinal andtransverse abdominal section, providing wide access to the liver and tothe spleen.

Example 3a Diffuse Bleeding

The surface of the liver was injured using sandpaper, producing diffusebleeding. The formulation essential to the invention was applied to thesurface of the liver. After about 2 minutes the film had cured and hadstaunched the bleeding of the liver surface.

Example 3b Liver Resection

The tip of the left lobe of the liver was removed. This produced a cutarea of approximately 1 cm², running transversely through the hepatictissue, with severe bleeding. The formulation essential to the inventionwas applied, and staunched the bleeding within 2 minutes.

Example 3c Pulmonary Aspiration

The rib cage was opened by medial sternotomy and widened with aright-lateral thoracotomy. The tip of the middle lobe of the right-handlung was cut off, producing a wound area approximately 1 cm² in size.This resulted in strong venous and also strong arterial bleeding.Moreover, a medium-sized bronchus had been severed, resulting in an airleak. The tissue adhesive was applied to the wound area of the lung, andimmediately staunched the venous and the arterial bleeding. With regardto the air leak, a large air bubble formed in the adhesive and burst,and there continued to be a fistula of air. After about 1 minute a dropof the adhesive was applied again to the air leak and pressed downfirmly using a plastic spatula. This sealed the air leak.

After 3 minutes in all the film was cured and had successfully staunchedthe bleeds and sealed the air leak.

Example 3d Aspiration of the Ascending Aorta

The ascending aorta was exposed and prepared. The ascending aorta wasaspirated generously with a 0.5 mm thick needle, producing a squirtingbleed. The formulation essential to the invention was applied to thebleed and pressed gently onto the hole using a plastic spatula. Bleedingcame to a halt within 2 minutes.

In vivo experiments on haemostasis—animal model: pig

The experiment was carried out on a female 30 kg domesticated pig underinhalative mask anaesthesia. Incision of the skin was carried outventrally to the sternocleidomastoid muscle, on the left-hand side. Thecarotid aorta was exposed in the region of the bulb. The carotid aortais found to have a diameter of approximately 5-6 mm.

Example 3e Minor Arterial Bleeding

Using a scalpel, the carotid artery was opened in the region of the bulbby careful preparation in such a way that there was a minor squirtingbleed from the artery. After brief initial rinsing of the mixing canula,approximately 4 ml of the formulation essential to the invention wereapplied to the source of the bleeding, and compressed by means ofcompression through surrounding tissue, in particular through thesternocleidomastoid muscle. The bleeding halted after about 1½ min. Thesurrounding tissue had been bonded to the carotid artery. A pulse couldbe felt on the carotid artery, distal to the site of the incision.

Example 3f Severe Arterial Bleeding

Using vessel scissors, the carotid artery was opened over half thecircumference. In the course of this operation, a severe squirtingarterial bleed developed. 5 ml of the formulation essential to theinvention were applied to the site of the bleed and compressed with thesurrounding tissue over about 2 min. The bleeding came to a halt after 2minutes.

Example 3g Venous Bleeding

The right aural vein was opened using a scalpel over a length ofapproximately 10 mm, resulting in a severe bleed. The formulationessential to the invention was applied without compression. The bleedcame to a halt after about 1 minute.

1.-10. (canceled)
 11. A method comprising: I. providing a formulationcomprising A) an isocyanate-functional prepolymer obtained from A1) analiphatic isocyanate and A2) a polyol component having a number-averagemolecular weight of greater than or equal to 400 g/mol and an average OHfunctionality of 2 to 6, B) a curing component comprising B1) anamino-functional aspartic ester of the general formula (I)

where X represents an n-valent organic radical obtained by removing theprimary amino groups of an n-functional amine, R₁ and R₂ represent,independently of one another, an organic radical which contains noZerewitinoff-active hydrogen and n is an integer of at least 2 II.applying the formulation to a cell tissue; and III. curing theformulation such that the loss of blood (haemostatic) or tissue fluidsis staunched or leaks in cell tissues are sealed.
 12. The methodaccording to claim 11, wherein the curing component further comprisesorganic fillers which have a viscosity as measured to DIN 53019 at 23°C. in the range of from 10 to 6000 mPas.
 13. The method according toclaim 12, wherein the formulation further comprises reaction products ofthe isocyanate-functional prepolymers with the organic fillers.
 14. Themethod according to claim 11, wherein the formulation further comprisesreaction products of the isocyanate-functional prepolymers with theamino-functional aspartic esters.
 15. The method according to claim 14,wherein the formulation further comprises reaction products of theisocyanate-functional prepolymers with the organic fillers.
 16. Themethod according to claim 11, wherein the curing component furthercomprises organic fillers which have a viscosity as measured to DIN53019 at 23° C. in the range of from 10 to 6000 mPas and wherein theformulation further comprises reaction products of theisocyanate-functional prepolymers with the amino-functional asparticesters and the organic fillers.
 17. The method according to claim 11,wherein the polyol component has a number-average molecular weight of4000 to 8500 g/mol.
 18. The method according to claim 11, wherein thepolyol component comprises a polyalkylene oxide polyether.
 19. Themethod according to claim 13, wherein the polyalkylene oxide polyetherscontains from 60% to 90% of ethylene oxide-based units, based on thetotal amount of alkylene oxide units.
 20. The method according to claim12, wherein the organic fillers comprise polyether polyols.
 21. Themethod according to claim 11, wherein the cell tissue comprises human oranimal tissue.
 22. The method according to claim 11, wherein theformulation is applied in an in vivo application.
 23. The methodaccording to claim 11, wherein the formulation is applied in an in vitroapplication.
 24. A method of staunching the loss of blood (haemostatic)or tissue fluids or of sealing leaks in cell tissues, which comprisesapplying a formulation to a cell tissue and then curing, wherein theformulation comprises A) an isocyanate-functional prepolymer obtainedfrom A1) an aliphatic isocyanate and A2) polyols having number-averagemolecular weights of greater than or equal to 400 g/mol and average OHfunctionalities of 2 to 6; and B) reaction products of theisocyanate-functional prepolymers with B1) an amino-functional asparticester of the general formula (I)

where X represents an n-valent organic radical obtained by removing theprimary amino groups of an n-functional amine, R₁ and R₂ represent,independently of one another, an organic radical which contains noZerewitinoff-active hydrogen and n is an integer of at least 2 andoptionally reaction products of the isocyanate-functional prepolymerswith B2) organic fillers which have a viscosity as measured to DIN 53019at 23° C. in the range of from 10 to 6000 mPas.